Treatment of celiac disease: expected outcomes and how to address the refractory patient Joseph A Murray The Mayo Clinic Rochester, MN 55906

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1 Treatment of celiac disease: expected outcomes and how to address the refractory patient Joseph A Murray The Mayo Clinic Rochester, MN OBJECTIVES 1. To outline the expected results of treatment with a gluten free diet. 2. To outline the approach to patients with a diagnosis of celiac disease who have persistent or recurrent symptoms despite a gluten-free diet. 3. Define the role for associated diseases in the cause of symptoms. 4. To recognize complications of celiac disease 5. To define the new and evolving classification of refractory celiac disease(sprue) and its relationship to enteropathy-associated lymphoma 6. To describe management strategies for ill patients with refractory sprue INTRODUCTION Celiac disease is a common disorder effecting almost 1% of the population, though only a fraction of these are diagnosed. Most (95%) patients with initially symptomatic celiac disease will have a durable response to a gluten-free diet. This response will include correction of malabsorption, relief of symptoms, and normalization of serological abnormalities. [1] Histological recovery may take a year or more in adults and frequently is incomplete even when other parameters recover. [2] Approximately 5% of patients will have persistent or recurrent symptoms of malabsorption, with villous atrophy, despite apparent adherence to a gluten-free diet. Intermittent symptoms due to the of difficulty with adherence to a gluten-free diet is likely much more common problem.[3] Several case histories will be used to illustrate the common and uncommon but serious scenarios that can occur in patients who have a diagnosis of celiac disease. I will first address the common scenario of non responsive celiac disease and then the less common but serious issue of refractory sprue. NON-RESPONSIVE CELIAC DISEASE The non-response celiac disease patients can be defined as a patient with a diagnosis of celiac disease who has been started on a gluten free diet but has persistent or recurrent symptoms despite self-declared adherence to a gluten free diet (GFD). It is first important to define if the patient ever had a response to the GFD. A failure to have a response should raise the possibility of an alternative diagnosis. 1. Revisit the Original Diagnosis When first faced with a patient, it is important to review the original diagnosis. It is important to re-review the original biopsy slides to verify that there was not a problem with inadequate sampling, malorientation, and missed alternative diagnosis or over interpretation of minor changes such as lymphocytic duodenosis. It is not unreasonable to request a pathological consultation for the biopsies though reviewing the biopsies directly with the pathologist may be very helpful.

2 Identify if any serology was done at the time of diagnosis before withdrawal of gluten from the diet. Negative serology, especially if done with a sensitive and specific test such as tissue transglutaminase antibody, taken before gluten was restricted by the patient, makes the diagnosis suspect. However, a negative test that occurred after the patient had reduced or restricted gluten intake is less useful in this regard. A positive test taken at any time is useful as adjunctive evidence. This illustrates the importance of obtaining serology even in biopsy-detected individuals before starting the GFD. Other information that may be helpful includes a family history of conformed celiac disease of dermatitis herpetiformis, or prediagnosis foreign travel a location where tropical sprue is a risk. Celiac disease can be considered highly probable based on, biopsies showing at least some villous atrophy, with crypt hyperplasia and intraepithelial lymphocytosis and at least one of the following: a partial response to a gluten-free diet; positive tissue transglutaminase or endomysial antibodies; and/or a positive family history of biopsy-confirmed celiac disease or dermatitis herpetiformis. 2. Determine Dietary Compliance The next step would be to identify if these patients have truly excluded gluten from their diet. Firstly usually the gastroenterologist can detect of the patient is deliberately ingesting by direct but tactful inquiry. Direct confrontation may illicit a denial, however after expressing some empathy with how difficult the diet most be many patients will admit to ingestion of gluten as often as several times a week. A little more difficult to detect is the inadvertent ingestion of gluten. Specifically inquiring about the intake of common commercial cereals such as Rice Krispies or Corn Flakes (other than the specifically manufactured and labeled gluten free kind) suggests that the patient is not aware of the hidden sources of gluten in the diet. A systematic review by a dietitian experienced in celiac disease can be invaluable to detect most cases of inadvertent gluten ingestion as well to aid with improving compliance.[4] Follow-up serologic testing using tissue transglutaminase or endomysial antibody is helpful and should show at least a substantial drop in the level of positivity or a negative result by 6-12 months. However different test kits used and normal ranges can make this difficult to gauge whether moderate drops in titers are significant. Persistently positive tests suggest substantial gluten ingestion, though a negative test des not rule out quantities of 1 gram or less, which is still enough to cause persistent villous damage and symptoms. 3. HLA Class 2 typing Patients can be tested to see if they carry the HLA class II genes that virtually required for celiac disease to occur. This should be done by a genotyping as the older serological methods are not accurate enough. The utility of typing the class 2 typing is to identify individuals who do not carry the HLA types associated with celiac disease. If these genes that encode DQ2 or DQ8 are lacking, especially in patients who were negative for tissue transglutaminase or endomysial antibodies or in whom these serologic tests were not done at the time of diagnosis, then again a search for other causes of the sprue-like condition should be sought. There are rare exceptions to this however. Those who not only carry the at risk type DQ2 but are homozygotes are at a higher likelihood of celiac disease but also in one study of developing refractory celiac disease or EATL. [5]

3 4. Alternative Diagnoses Sometimes the review of the initial diagnosis will raise the possibility of alternative diagnoses. (Table 1) Table 1: Differential diagnosis of villous atrophy Tropical Sprue Peptic duodenitis with inadequate sampling Combined variable immunoglobulin deficiency Severe giardiasis ( especially with IgA deficiency) HIV enteropathy Graft versus host disease Chronic ischemia Autoimmune enteropathy NSAID injury Crohn s disease Radiation enteritis Whipple s disease IPSID Self limited enteritis Other food protein intolerances ( children) IPEX ( children) These possibilities are wide but could include combined variable immunoglobulin deficiency which itself can cause sprue. Clues to this diagnosis may be completely negative serology at initial diagnosis and measurement of quantitative immunoglobulin levels especially deficiencies of more than one immunoglobulin isotype. Other possible entities that could occur in this circumstance would be autoimmune enteropathy, non-steroidal anti-inflammatory drug-induced enteritis, so-called self-limited enteritis, or rarely ischemia, Whipple s disease or other disorders that usually have a fairly classic histopathologic appearance. 5. Additional /Associated Diagnoses Assuming that the patient is still likely to have celiac disease and no alternative diagnosis has been made in the foregoing steps, searching for an associated disorder is directed by what predominant symptom the patient has. If it is diarrhea then colon biopsies may find microscopic colitis. Recurrent anemia may be a manifestation of unhealed celiac disease, poor intake, achlorhydria, colon neoplasia, aspirin or NSAID use or rarely small intestinal malignancy including adenocarcinoma. Persistent steatorrhea may suggest pancreatic insufficiency, though I would not assume that until I had re-biopsied the small intestine. Abdominal pain can be due any of the usual causes but remember that celiac disease can be associated with gallstones, duodenal strictures and ulcers, recurrent pancreatitis and motility disturbances.[6, 7] 6. Push/ Extended Endoscopy Unless the evaluation of patients has not revealed some other ready explanation for the symptoms and the patient has been on the gluten free diet for at least 6 months and celiac disease continues to be the presumptive diagnosis, the next step is to undertake a repeat endoscopy preferably with an extended or push enteroscope.[8] This will allow the endoscopist

4 to examine not only the duodenum but the proximal jejunum visually and to obtain multiple samples sufficient for histologic examination, for which samples are fixed in formalin, mounted in paraffin and stained by standard H&E staining and compared with the original pre-treatment biopsies. It may be helpful to save additional biopsies at the time of this endoscopy that are frozen and kept for detailed immunological studies including possible T gene rearrangement. If the biopsies show no significant improvement over the original pre-treatment biopsies with continued inflammation and infiltration of the surface layer with intraepithelial lymphocytes associated with villous atrophy, then immunohistochemical stains to identify aberrant immunophenotype of these IELs maybe undertaken. [9] During the same extended upper endoscopy, an aspirate can be obtained for bacterial overgrowth and whilst the prevalence of bacterial overgrowth in the circumstance varies from 10 to 50%, the demonstration of bacterial overgrowth by quantitative culture, does not exclude the possibility of other explanations for the patient s symptoms such as lymphocytic colitis. In most cases of non responsive celiac disease, the systematic evaluation, as described above, reveals either gluten contamination, an alternative or additional diagnosis. Even in referral populations, only a minority of patients have true refractory celiac disease. When it does not and there is continued villous atrophy then refractory celiac disease is the major concern. Figure 1: Approach to non-responsive celiac disease

5 REFRACTORY SPRUE Refractory sprue can defined as clinical malabsorption associated with continued enteropathy consistent with a sprue-like picture despite the patient adhering to a strict gluten-free diet. Each of these 3 conditions need to be met before embarking on the detailed evaluation called for and indeed justified by a substantial morbidity and mortality of refractory sprue. Typically it is an older patient over the age of 50 years who has lost substantial weight has steatorrhea and diarrhea, negative serology currently and is clinically failing despite strict adherence to a gluten free diet and if applicable treatment of additional diagnosis. Refractory celiac disease has been divided into 2 types. Type 1 refractory celiac disease is defined by the above criteria. Type 2 refractory celiac disease is a similar to type one except there is evidence that identifies an abnormal phenotype of intraepithelial lymphocyte that is clonally expanded. IDENTIFICATION OF ABERRANT IEL PHENOTYPE It has been shown now for over seven years that the intraepithelial lymphocytes in refractory sprue may undergo a switching of their immunophenotype from T cell markers to NK cell markers. Specifically, these cells lose the surface expression of CD3 though they maintain cytoplasmic expression. They lose the surface expression of CD8 and the T cell receptor βf1. Immunohistological stains if they show a substantial proportion (greater than 50%) of intraepithelial lymphocytes have intracellular CD3 staining but lack surface CD8 or βf1 staining; this suggests that there has been a clonal transformation of these cells. [9] It is thought that many, though not all of the lymphomas that occur to complicate celiac disease, arise from this immunophenotype. These aberrant lymphocytes can also spread to the stomach, colon peripheral blood and rarely to the skin. While these cells do not have cytological features of neoplastic cells they can develop chromosomal abnormalities specifically trisomy 1q. These cells that typify refractory celiac disease type 2 are considered by some to be a cryptic lymphoma based on their development of aberrant phenotype, clonality of the t-cell receptors and the chromosomal abnormalities. Clonal T cell receptor gene rearrangement may be identifiable on the biopsies by PCR. This may be done on formalin fixed tissues if adequate DNA can be extracted from the blocks. If frozen samples are available the PCR findings can be confirmed by southern blotting. The demonstration of clonality itself is not sufficient for a designation Type 2 refractory sprue though a careful search for other evidence for an abnormal phenotype t cell population is needed and close follow up needed. Some centers now routinely use flow cytometry on lymphocytes derived from fresh biopsies to identity aberrant lymphocytes. The methods are not yet standardized or in common use as yet. The method that has been used by the Dutch group isolates cels from fresh intestinal biopsies. The cells are gated for CD45 and the homing receptor CD103 that identifies intraepithelial origin on the cells. Then 4 color flow cytometry for surface CD3, CD4 CD8, CD7, CD16/56, CD19 and the gd TCR along with cytoplasmic CD3 is undertaken. A threshold of 10% of the CD103

6 + that have the aberrant phenotype (surface CD3-, CD8-, and cytoplasmic CD3+) signifies a significant expansion. SMALL BOWEL IMAGING The primary role of imaging is to identify complications in the intestine either malignant or non malignant or detect extra intestinal manifestations of malignancy. These can be divided into advanced endoscopic imaging methods such as capsule endoscopy or double balloon enteroscopy and radiographic methods such as CT enterography, small bowel contrast studies or more recently MR enterography or PET scanning. If the endoscopy is in parallel with the endoscopic examination, some other imaging of the small intestine should be considered. CT enterography, small bowel contrast studies, or more recently capsule endoscopic or double balloon enteroscopy have been applied in the setting of refractory sprue and may identify enteropathy associated lymphoma, malignant or benign strictures or obstructions, intussusception, ulcerative jejunoileitis or some other malignant state within the intestine. Standard CT or MR scanning may detect enlarged lymph nodes or masses that suggest neoplastic transformation. However, mesenteric lymphadenopathy alone can occur due to uncomplicated celiac disease alone though it usually shrinks after institution of a gluten free diet. Ct scanning may detect a small spleen that may be associated with a greater risk of lymphoma and indicates a need for vigilance for infection risk and vaccination.[10] PET Scanning may be helpful in detecting EATL in patients with refractory sprue. MANAGEMENT OF REFRACTORY CELIAC DISEASE The work up for these problems has been largely limited to centers that have both the clinical expertise and laboratory to undertake a complete evaluation and early referral is encouraged. Figure 2: approach to refractory sprue

7 TYPE 1 REFRACTORY CELIAC DISEASE Type 1 refractory sprue is defined as refractory sprue but without evidence of an aberrant T cell clone. It is still possible but unlikely that these patients may develop a lymphoma. The evaluation is similar except without the need for the search of a systemic spread of these abnormal lymphocytes. There may be overlap between this type of refractory celiac disease, especially if the patients never responded to a gluten-free diet, with autoimmune enteropathy. Autoimmune enteropathy may be distinguished from celiac disease by: 1) lack of the HLA type s ( DQ2 or DQ8) that define risk for celiac disease; 2) a paucity of goblet cells on biopsies; 3) a relative lack of intraepithelial lymphocytosis by comparison to celiac disease; 4) circulating autoantibodies directed against surface mucosa. Nevertheless, both conditions are treated similarly with steroids and immunosuppressives.( Akram et al, submitted) Type 1 refractory celiac disease usually responds to immunosuppression with steroids and Azothioprine for steroid-sparing effect. Recent reports suggest that patients may also respond to budesonide though the dosing would need to be altered to increase the likelihood of approximal mucosal distribution of the medication. [11] TYPE 2 REFRACTORY SPRUE This particular form is thought by some to be a cryptic lymphoma or at least a pre-lymphomas. [12] It occurs likely as a consequence of both the initial proliferative effect of gluten on the t cells but also an accumulation of genetic defects that favor continued proliferation despite the removal of gluten. The cells of origin are the intraepithelial lymphocytes that under go progressive changes that result in loss of there surface t cell markers CD3, CD8 and TCR, but preservation of cytoplasmic CD3. If these cells exceed a certain percentage (20%) of the IELS that express CD7, CD103 then that indicates a substantial population of phenotypically aberrant cells. It has been suggested that patients with these particular findings have a particularly high mortality and a high likelihood of progression or transformation to enteropathy-associated T cell lymphoma no matter what the treatment used to suppress the symptoms. If the aberrant phenotype is identified on the small bowel biopsies, then a search for systemic spread to the blood and bone marrow is probably justified. Also, careful body imaging and/or endoscopic examination of the small intestine may be justified looking for synchronous tumors in the intestine. Type 2 refractory sprue has a much more guarded prognosis with an uncertain outcome. In patients, either systemic steroids or topically active steroids might be helpful in suppressing symptoms. It is more controversial as to what the role of azathioprine or other immunosuppressives or cytotoxic agents are in this circumstance. Whilst these patients might be respond to immunosuppression, there may be at least theoretically an increased risk of malignancy in the context of immunosuppression. [13] In very ill patients who are refractory to immunosuppression, it may be justified to consider treating these patients as though they have an evolved lymphoma. Chemotherapy directed against T cells has also been tried but may only serve as a temporary suppression of symptoms. [14] There is some recent evidence to justify the use of myeloablative chemotherapy with stem cell transplantation and possibly bone marrow transplant. [15]

8 NUTRITIONAL SUPPORT Patients with refractory sprue are often very ill, have multiple deficiency states both of protein calorie malnutrition as well as micronutrient deficiencies. Careful evaluation for deficiencies including, but not limited to iron, B12, folic acid, zinc, copper as well as electrolyte deficiencies, particularly magnesium, need to be sought and managed aggressively. Vitamin D deficiency and osteomalacia also maybe especially common in these patients and again may need to be managed with malabsorption doses of vitamin D. Patients who cannot achieve their nutritional needs by oral means may require enteral feeding or even if this is unsuccessful, parenteral nutrition.[16] However, even successful maintenance of patients on parenteral nutrition should not be a cause for complacency as mortality may still be quite high in these patients and definitive or continued search for a therapy directed at the small intestine should be continued. ENTEROPATHY ASSOCIATED T-CELL LYMPHOMA (EATL) Enteropathy associated enteropathy ( EATL) may be the end result of a process that starts with a gluten driven t cell proliferation that defines celiac disease. In the face of persistent activation and possibly wit the collusion of the effects of interleukin 15 produced in response to the innate response to gluten, the IELS may acquire sequential genetic changes and eventually chromosomal changes that lead to the development of an aberrant phenotype described above. These cells lose their dependence on gluten and may become neoplastic. Patients with a delay in diagnosis of celiac disease despite persisting severe symptoms and those who have been non compliant with the GFD are substantially increased risk of celiac disease. [17] While EATL may arise in the setting of villous atrophy however it can also appear in healed celiac disease. The presentation of EATL can be either be as an acute event such as perforation, obstruction or bleeding often occurring in the absence of a preceding diagnosis of celiac disease or may cause a gradual and indeed inexorable progressive malabsorption in someone with a prior diagnosis of celiac disease. The outcome may be a little better for those that present in the acute type with occasional prolonged remissions. [18] Once EATL occurs the outlook is grim with five year survival is 10-20%. Patients often succumb to infections may be in a very poor shape to tolerate aggressive chemotherapy. MISCELLANEOUS ISSUES Hyposplenism may be particularly common in patients with refractory celiac disease and vigilance for infective complications is necessary. Most would recommend pneumococcal vaccination. If chemotherapy is being entertained, it would probably be prudent to consider antibiotic prophylaxis as well as a high vigilance for encapsulated organism infections. PROGNOSIS The prognosis of most cases of non responsive celiac disease is good so long as treatable causes can be found. Once refractory sprue has been diagnosed the prognosis varies depending on whether there are aberrant t cells or not. Those with type one RCD usually have a good response to steroids and immunosuppressives, whilst those with type 2 RCD have a much more guarded outlook. Nutritional support may be crucial in supporting the ill patients to withstand therapies

9 that otherwise would be difficult to sustain in the face of severe malabsorption. The prognosis for EATL is dismal though occasional long remissions occur.

10 REFERENCES 1. Murray, J.A., et al., Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease. American Journal of Clinical Nutrition, (4): p Lee, S.K., et al., Duodenal histology in patients with celiac disease after treatment with a gluten-free diet. Gastrointest Endosc, (2): p Fine, K.D., R.L. Meyer, and E.L. Lee, The prevalence and causes of chronic diarrhea in patients with celiac sprue treated with a gluten-free diet [see comments] [published erratum appears in Gastroenterology 1998 Feb;114(2):424-5]. Gastroenterology, (6): p Abdulkarim, A.S., et al., Etiology of nonresponsive celiac disease: results of a systematic approach. American Journal of Gastroenterology, (8): p Al-Toma, A., et al., Human Leukocyte Antigen-DQ2 Homozygosity and the Development of Refractory Celiac Disease and Enteropathy-Associated T-Cell Lymphoma. Clinical Gastroenterology and Hepatology, (3): p Patel, R.S., F.C. Johlin, Jr., and J.A. Murray, Celiac disease and recurrent pancreatitis. Gastrointestinal Endoscopy, (6): p Schweiger, G.D. and J.A. Murray, Postbulbar duodenal ulceration and stenosis associated with celiac disease. Abdominal Imaging, (4): p Cellier, C., et al., Push enteroscopy in celiac sprue and refractory sprue. Gastrointestinal Endoscopy, (5): p Patey-Mariaud De Serre, N., et al., Distinction between coeliac disease and refractory sprue: a simple immunohistochemical method. Histopathology, (1): p Di Sabatino, A., et al., Splenic hypofunction and the spectrum of autoimmune and malignant complications in celiac disease. Clinical Gastroenterology & Hepatology, (2): p Daum, S., et al., Therapy with budesonide in patients with refractory sprue. Digestion, (1): p Mulder, C.J., et al., Refractory coeliac disease: a window between coeliac disease and enteropathy associated T cell lymphoma. Scandinavian Journal of Gastroenterology - Supplement, 2000(232): p Maurino, E., et al., Azathioprine in refractory sprue: results from a prospective, open-label study. Am J Gastroenterol, (10): p Al-toma, A., et al., Cladribine Therapy in Refractory Celiac Disease With Aberrant T Cells. Clinical Gastroenterology and Hepatology, (11): p Al-toma, A., et al., Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells. Blood, (5): p Scolapio, J.S., et al., Survival of home parenteral nutrition-treated patients: 20 years of experience at the Mayo Clinic. Mayo Clinic Proceedings, (3): p Holmes, G.K., et al., Malignancy in coeliac disease--effect of a gluten free diet. Gut, (3): p Egan, L.J., et al., Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era. Journal of Clinical Gastroenterology, (2): p